The gene for Cystic Fibrosis, the most common lethal genetic disorder in Caucasians, has recently been localized to the middle of the long arm of chromosome 7 (q2.1-q3.1). The long-term objective of this research plan is to understand the molecular basis of Cystic Fibrosis. We will proceed by pursuit of the following aims: 1). To identify an affected individual with a chromosomal deletion or rearrangement involving the CF gene using macro- restriction mapping using the tightly linked, flanking DNA probes Met and D7S8 (J3.11). Any area of rearranged DNA will be explored for the gene which causes CF. 2). To characterize a Met H/Not I polymorphism (discovered with pulse field gel electrophoresis) by pedigree studies and screening of normal individuals. Families that have a known crossover between Met and CF will be tested for the Not I polymorphism and if present, to determine whether the site has recombined with the CF gene or the Met locus. The Not I polymorphism will also be used to clone DNA fragments that contain the Not I restriction sites identified by the Met probe from a human chromosome 7 mouse hybrid cell line. These will then be employed in the search for a deletion and to create a macro-restriction map of the CF locus. 3). To determine the haplotypes defined by the CF-linked polymorphic sites in affected and normal individuals from populations in which CF is uncommon (i.e., Black, Oriental), then to evaluate the extent of linkage disequilibrium of these haplotypes with the CF locus. These data will be compared to those derived from the European population to assess inter- population variation and/or similarities in the haplotypes associated with CF gene. 4). When the CF gene is isolated, to discover the mutant allele or alleles and develop direct detection strategies to allow population screening for heterozygotes.